title: Mitochondrial cumulative damage induced by mitoxantrone: late onset cardiac energetic impairment.
abstract: Mitoxantrone (MTX) is a chemotherapeutic agent, which presents late irreversible cardiotoxicity. This work aims to highlight the mechanisms involved in the MTX-induced cardiotoxicity, namely the effects toward mitochondria using in vivo and in vitro studies. Male Wistar rats were treated with 3 cycles of 2.5 mg/kg MTX at day 0, 10, and 20. One treated group was euthanized on day 22 (MTX22) to evaluate the early MTX cardiac toxic effects, while the other was euthanized on day 48 (MTX48), to allow the evaluation of MTX late cardiac effects. Cardiac mitochondria isolated from 4 adult untreated rats were also used to evaluate in vitro the MTX (10 nM, 100 nM, and 1 μM) direct effects upon mitochondria functionality. Two rats of MTX48 died on day 35, and MTX treatment caused a reduction in relative body weight gain in both treated groups with no significant changes in water and food intake. Decreased levels of plasma total creatine kinase and CK-MB were detected in the MTX22 group, and increased plasma levels of lactate were seen in MTX48. Increased cardiac relative mass and microscopic changes were evident in both treated groups. Considering mitochondrial effects, for the first time, it was evidenced that MTX induced an increase in the complex IV and complex V activities in MTX22 group, while a decrease in the complex V activity was accompanied by the reduction in ATP content in the MTX48 rats. No alterations in mitochondria transmembrane potential were found in isolated mitochondria from MTX48 rats or in isolated mitochondria directly incubated with MTX. This study highlights the relevance of the cumulative MTX-induced in vivo mitochondriopathy to the MTX cardiotoxicity.
authors.affiliation: REQUIMTE, Laboratório de Toxicologia, Departamento de Ciências Biológicas, Faculdade de Farmácia, Universidade do Porto, Porto, Portugal, luciana.g.rossato@gmail.com.
authors.forename: Luciana Grazziotin
authors.initials: LG
authors.lastname: Rossato
authors.forename: Vera Marisa
authors.initials: VM
authors.lastname: Costa
authors.forename: Eliane
authors.initials: E
authors.lastname: Dallegrave
authors.forename: Marcelo
authors.initials: M
authors.lastname: Arbo
authors.forename: Renata
authors.initials: R
authors.lastname: Silva
authors.forename: Rita
authors.initials: R
authors.lastname: Ferreira
authors.forename: Francisco
authors.initials: F
authors.lastname: Amado
authors.forename: Ricardo Jorge
authors.initials: RJ
authors.lastname: Dinis-Oliveira
authors.forename: José Alberto
authors.initials: JA
authors.lastname: Duarte
authors.forename: Maria
authors.initials: M
authors.lastname: de Lourdes Bastos
authors.forename: Carlos
authors.initials: C
authors.lastname: Palmeira
authors.forename: Fernando
authors.initials: F
authors.lastname: Remião
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D015415:Biomarkers / Q000097:blood; D003576:Electron Transport Complex IV / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects*; D006331:Heart Diseases / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology; D008297:Male; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008929:Mitochondria, Heart / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008942:Mitoxantrone / Q000633:toxicity*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D015430:Weight Gain / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D015415:Biomarkers; D000255:Adenosine Triphosphate; D008942:Mitoxantrone; D003576:Electron Transport Complex IV